CDC6 (cell division cycle 6 homolog (S. cerevisiae))

2008-01-01   Michael Zachariadis , Vassilis G Gorgoulis 

University of Athens, Faculty of Medicine, Department of Anatomy (MZ) ; Department of Histology, Embryology, Molecular Carcinogenesis Group (VGG)





The gene starts at 35697672 bp from pter and ends at 35712939 bp from pter. Its size is 15267 bases and its orientation lie at the plus strand.
The 5 promoter region contains putative sites for transcriptional control, including an initiator element, a CHR element, two main binding sites for E2F, a putative Sp1 site, and a CCAAT region. No consensus TATA box is evident. This resembles the organization of other genes encoding proteins associated with the G1/S transition.


The gene has 12 exons. The five putative transcripts (see table below) encode the same product of 560aa. There are about 230 EST sequences.
Accession N°Transcript length (bp)Notes
NM_001254 3053RefSeq


there are no known pseudogenes



The CDC6 protein or p62 is composed of 560 amino acids with a molecular weight of 62720 Da. The central portion of the protein contains a conserved nucleotide binding/ATPase domain, which classifies it to a large superfamily of ATPases known as "ATPases associated with various cellular activities" (AAA) proteins and specifically to the AAA+ subfamily. The Walker-A motif GXXGXGK(T/S) (nucleotide binding) of the AAA+ domain spans aa 202-209, while the Walker-B motif D(D/E)XX (nucleotide hydrolysis) spans aa 284-287. The domain contains also a leucine zipper (aa 306-327), and a caspase dependent cleavage site DQL290DS.
The N-terminal domain contains: three consensus phosphorylation sites at serine (S)54, S74 and S106, which are phosphorylated in vivo by CDK-related activity at the G1/S boundary; a putative conserved nuclear localization sequence ((S/T)PXK57R58(L/I)); two putative destruction boxes (D-box (aa 56-64) and KEN box (aa 81-83)), which target CDC6 for proteolysis by APCCDH1 during early G1 or G0, but not S, G2 or M; and a cyclin binding domain mapped to a Cy-motif (aa 93-100) that is similar to the cyclin binding regions in p21/WAF1/SDI1 and E2F-1.
The C-terminal domain contains: a putative classical nuclear export signal (NES) between residues 462-488 (ILVCSLMLLIRQLKI), a caspase dependent cleavage site SEV442DG, and a conserved winged-helix domain (WHD) with unknown function; it possibly mediates protein-protein interactions or a direct interaction with the DNA helix.


It is expressed in all proliferating cells but not in quiescent or differentiated cells.


Even though it was believed at first that p62CDC6 was nuclear during G1 and cytoplasmic during S and G2, lately it has been found that there is an endogenous fraction of the protein that remains chromatin-bound throughout the cell cycle.


- ATP binding
- Chromatin binding
- Nucleoside-triphosphatase activity
- Nucleotide binding
- Protein binding
- Loading factor for MCM2-7: Cdc6/Cdc18 is recruited to replication origins by ORC. Once localized at replication origins, Cdc6 helps to recruit and load MCM factors onto DNA in a process that requires CDC6-mediated ATP hydrolysis. After loading of MCM2-7 on DNA, CDC6 is not necessary for origin firing and dissociates from the complex, through a phosphorylation-dependent procedure. It seems though that CDC6 has additional roles related to S/M checkpoint control. Accumulating evidence suggests that CDC6 is required for proper control of mitotic entry. Deregulation of CDC6 results in mitotic block, aberrant mitotic progression, or apoptosis.





No known mutations

Implicated in

Entity name
Because of its key role in DNA replication, deregulation of CDC6 could lead to genomic instability fueling the risk for neoplastic transformation. Indeed, CDC6 upregulation has been observed in many cancerous lesions, including brain tumors, non-small cell lung carcinomas, mantle cell lymphomas, and various cervical neoplasias. Interestingly, in aggressive prostate cancer, CDC6 is downregulated.
CDC6 encompasses certain oncogenic characteristics that manifest themselves when CDC6 expression is deregulated. For example, CDC6 induces DNA replication in quiescent cells, while in certain occasions overexpression of CDC6 leads to DNA overreplication in tumour cells.
While cells have mechanisms to prevent aberrant DNA replication, deregulation of CDC6, or /and its partner in pre-RCs, CDT1 may lead to abrogation of the antitumor barriers of senescence and apoptosis. In addition their stable expression in premalignant papilloma cells lead to transformation of these cells, which upon injection into nude mice produce tumors, an activity that clearly portrays the oncogenic potential of CDC6 deregulation.
Moreover, deregulation of CDC6 may lead to inactivation of the INK4/ARF locus through recruitment of histone deacetylases HDAC1 and HDAC2 and heterochromatinization of the INK4/ARF locus. This locus encodes the tumour suppressor genes p16INK4a, p15INK4b, and ARF, and inactivation of this locus is closely related to cancer.


Pubmed IDLast YearTitleAuthors
161792492005CDKs give Cdc6 a license to drive into S phase.Ayad NG et al
171360932006Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.Bartkova J et al
118468072002Synthesis and turn-over of the replicative Cdc6 protein during the HeLa cell cycle.Biermann E et al
120066512002Targeted destruction of DNA replication protein Cdc6 by cell death pathways in mammals and yeast.Blanchard F et al
122967512002Immunohistochemical localization of cdc6 in squamous and glandular neoplasia of the uterine cervix.Bonds L et al
180483872008CDC6: from DNA replication to cell cycle checkpoints and oncogenesis.Borlado LR et al
125546702003Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1.Clay-Farrace L et al
146729322004The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells.Cook JG et al
118053052002Analysis of Cdc6 function in the assembly of mammalian prereplication complexes.Cook JG et al
108061042000Chromatin-bound Cdc6 persists in S and G2 phases in human cells, while soluble Cdc6 is destroyed in a cyclin A-cdk2 dependent process.Coverley D et al
113466502001Multiple mechanisms regulate subcellular localization of human CDC6.Delmolino LM et al
160557072005p53-Dependent regulation of Cdc6 protein stability controls cellular proliferation.Duursma A et al
117798702002Nuclear organization of DNA replication initiation proteins in mammalian cells.Fujita M et al
104643371999Cell cycle regulation of human CDC6 protein. Intracellular localization, interaction with the human mcm complex, and CDC2 kinase-mediated hyperphosphorylation.Fujita M et al
165721772006Oncogenic activity of Cdc6 through repression of the INK4/ARF locus.Gonzalez S et al
175679512007Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage.Hall JR et al
97746821998Cell cycle-regulated expression of mammalian CDC6 is dependent on E2F.Hateboer G et al
111025122000Mutation of cyclin/cdk phosphorylation sites in HsCdc6 disrupts a late step in initiation of DNA replication in human cells.Herbig U et al
104360181999The Cdc6 nucleotide-binding site regulates its activity in DNA replication in human cells.Herbig U et al
103395641999Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6.Jiang W et al
154663992004Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1.Karakaidos P et al
164399992006The functional role of Cdc6 in S-G2/M in mammalian cells.Lau E et al
180068352007Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.Liontos M et al
110461552000Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis.Méndez J et al
161537032005CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis.Mailand N et al
156961262005Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix.Murphy N et al
114963172001Cdc6 expression as a marker of proliferative activity in brain tumors.Ohta S et al
97780431998Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F.Ohtani K et al
126283422003Down to the origin: Cdc6 protein and the competence to replicate.Pelizon C et al
109953892000Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1.Petersen BO et al
170363322006Unbalanced expression of licensing DNA replication factors occurs in a subset of mantle cell lymphomas with genomic instability.Pinyol M et al
120065852002Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer.Robles LD et al
95668951998Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase.Saha P et al
163225582005Recruitment of ORC or CDC6 to DNA is sufficient to create an artificial origin of replication in mammalian cells.Takeda DY et al
102149641999Identification of the sequence responsible for the nuclear localization of human Cdc6.Takei Y et al
127188852003A p53-dependent checkpoint pathway prevents rereplication.Vaziri C et al
89901751997A human protein related to yeast Cdc6p.Williams RS et al
95204121998Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.Yan Z et al
168013882006Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells.Yim H et al

Other Information

Locus ID:

NCBI: 990
MIM: 602627
HGNC: 1744
Ensembl: ENSG00000094804


dbSNP: 990
ClinVar: 990
TCGA: ENSG00000094804


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cell cycleKEGGko04110
Cell cycleKEGGhsa04110
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
Activation of ATR in response to replication stressREACTOMER-HSA-176187
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G0 and Early G1REACTOMER-HSA-1538133
G1/S TransitionREACTOMER-HSA-69206
G1/S-Specific TranscriptionREACTOMER-HSA-69205
Activation of the pre-replicative complexREACTOMER-HSA-68962
E2F mediated regulation of DNA replicationREACTOMER-HSA-113510
Synthesis of DNAREACTOMER-HSA-69239
Switching of origins to a post-replicative stateREACTOMER-HSA-69052
Orc1 removal from chromatinREACTOMER-HSA-68949
CDK-mediated phosphorylation and removal of Cdc6REACTOMER-HSA-69017
Regulation of DNA replicationREACTOMER-HSA-69304
Association of licensing factors with the pre-replicative complexREACTOMER-HSA-69298
Removal of licensing factors from originsREACTOMER-HSA-69300
M/G1 TransitionREACTOMER-HSA-68874
DNA Replication Pre-InitiationREACTOMER-HSA-69002
Assembly of the pre-replicative complexREACTOMER-HSA-68867
CDC6 association with the ORC:origin complexREACTOMER-HSA-68689
CDT1 association with the CDC6:ORC:origin complexREACTOMER-HSA-68827
DNA ReplicationREACTOMER-HSA-69306

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
180068352007Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.78
180483872008CDC6: from DNA replication to cell cycle checkpoints and oncogenesis.73
175679512007Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage.62
193430712009Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle.41
222011242011Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins.36
117798702002Nuclear organization of DNA replication initiation proteins in mammalian cells.34
125546702003Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1.31
160557072005p53-Dependent regulation of Cdc6 protein stability controls cellular proliferation.30
147493772004Cdc6 chromatin affinity is unaffected by serine-54 phosphorylation, S-phase progression, and overexpression of cyclin A.28
186175142008Cdt1 and Cdc6 are destabilized by rereplication-induced DNA damage.27


Michael Zachariadis ; Vassilis G Gorgoulis

CDC6 (cell division cycle 6 homolog (S. cerevisiae))

Atlas Genet Cytogenet Oncol Haematol. 2008-01-01

Online version: